Novel Pharmaceutical Formulation of Cefixime for Enhanced Bioavailability

ABSTRACT

A chewable tablet comprising Cefixime having a mean particle size between 20 μ and 120 μ wherein the said composition demonstrates bioequivalence to a suspension of Cefixime trihydrate. The process of preparation of the chewable tablet comprises the steps of optionally micronizing Cefixime such that the mean particle size of the Cefixime particles is between 20 μ and 120 μ, blending with other excipients, roll compaction, milling to form granules, blending to form a secondary blend and compression of the secondary blend to form tablets.

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical formulationcomprising Cefixime.

BACKGROUND OF THE INVENTION

Cefixime is a semi synthetic cephalosporin antibiotic for oraladministration. It was first disclosed in U.S. Pat. No. 4,409,214 byFujisawa Corporation, Japan. It is indicated for the treatment ofinfections caused by various gram—positive and gram—negative organismschiefly uncomplicated urinary tract infections caused by E. coli and P.mirabilis, otitis media caused by H. influenza, M. catarrhalis and S.pyogenes, acute bronchitis and exacerbations of chronic bronchitiscaused by S. pneumonia and H. influenza. It is also indicated foruncomplicated gonorrhea caused by N. gonorrhea. It is one of the mostprescribed drugs for pediatric use.

Cefixime is currently available in a number of different formulations,for instance as oral suspension and tablets. Different formulations anddifferent amounts of Cefixime are provided for adult and pediatricpatients for example as tablets comprising 200 mg and 400 mg Cefiximetrihydrate and as oral suspension comprising 100 mg/5 ml Cefiximetrihydrate.

From the point of view of bioavailability, the preferred form ofadministration of sparingly soluble medicaments such as beta lactamantibiotics is often an aqueous suspension. However, there arelimitations associated with this form of administration. For example, asmentioned in the product insert of “Suprax”, Cefixime, given orally, isabout 40%-50% absorbed whether administered with or without food. Theoral suspension, on the other hand, produces average peak concentrationsapproximately 25%-50% higher than the conventional tablets. The areaunder the time versus concentration curve is greater by approximately10%-25% with the oral suspension than with the conventional tablet afterdoses of 100 to 400 mg, when tested in normal adult volunteers. Thus, atthe same dosage strength, Cefixime tablets are not bioequivalent to thesuspension. Although suspensions are the common mode of administrationof Cefixime especially to the pediatric population, they suffer fromother disadvantages such as limited shelf life and lack of accuracy ofdose measurement. The bitter taste of many such medicaments is also adrawback. The bulky nature of the container often precludes ease ofcarriage and storage.

Thus, a need exists for developing a formulation of Cefixime, which doesnot suffer from the disadvantages of the suspension formulation aselaborated above.

Solid dosage forms that are swallowed such as tablets and capsulesprovide accurate dosage, avoid taste problems and are more amenable tobeing portable; but since they have to disintegrate in thegastrointestinal tract and the medicament has then to dissolve before itcan be absorbed, absorption tends to be slower than from a suspensionand may be less than complete leading to bioequivalence issues aspointed out earlier. Also, some patients have difficulty in swallowingtablets and capsules, and there is a practical limit to the size, andtherefore the dose, that can be swallowed. This is particularly true forgeriatric patients and children.

Thus, the challenge for us was to formulate a dosage form comprisingCefixime, which would have a bioavailability similar to that of asuspension comprising Cefixime, but without the attendant disadvantagesof suspension.

SUMMARY OF THE INVENTION

It has surprisingly been found that pharmaceutical compositionscomprising Cefixime trihydrate particles having a mean particle sizebetween 20 μ and 120 μ exhibit higher bioavailability and arebioequivalent to suspension formulations comprising Cefixime trihydrate.Accordingly, the invention relates to a pharmaceutical compositioncomprising Cefixime trihydrate particles having a mean particle sizebetween 20 μ and 120 μ as measured by Malvern light scattering, and apharmaceutically acceptable excipient such that the formulation isbioequivalent to an already marketed oral suspension formulationcomprising Cefixime trihydrate. The invention further provides achewable tablet formulation of Cefixime comprising chewable base,sweetener and flavorants wherein the mean particle size of Cefiximeparticles is between 20 μ and 120 μ.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for a chewable tablet comprising Cefiximetrihydrate particles having a mean particle size between 20 μ and 120 μ.

The term Cefixime as used alone also denotes the trihydrate salt and theterms can be used interchangeably for the purpose of this invention.

The tablet is provided for in a range of strengths of Cefixime i.e. 100,150, 200 and 300 mg of Cefixime as Cefixime trihydrate.

It is preferred that Cefixime particles have a mean particle sizebetween 20 μ and 120 μ. The term “mean particle size between 20μ and 120μ” as used herein refers to Cefixime particles having a d₅₀ valuebetween 20 μ and 120 μ. It is noted that the notation d_(x) means that X% of particles have a diameter less than the specified diameter D. Thus,for example, a d₅₀ of 20 μ for a particular sample of Cefixime meansthat 50% of the Cefixime particles in the said sample have a diameterless than 20 μ.

The term ‘particles’ refers to individual particles whether theparticles exist singly or are agglomerated. Thus, a compositioncomprising Cefixime may contain agglomerates that are well beyond thesize limit of about 120 μ specified herein. However, if the meanparticle size of the primary drug substance i.e. Cefixime trihydratecomprising the agglomerate is between 20 μ and 120 μ individually, thenthe agglomerate itself is considered to satisfy the particle sizeconstraints defined herein and the composition is within the scope ofthe invention.

The said particle size limit for Cefixime may be achieved by any of thesize reduction techniques known to those skilled in the art, forexample, micronization, milling and the like.

Cefixime trihydrate is present in the desired dosage form from about 10%to about 50% by weight of the tablet.

The chewable tablet base in accordance with the present invention maybeselected from those commonly known in the art. For example, it is one ormore selected from the group comprising xylitol, mannitol and sorbitol.It is present from about 25% to about 75% by weight of the tablet.

In addition to an excipient to provide a chewable base, the chewabletablet according to the present invention may optionally comprisefurther excipients for instance binders, disintegrants, lubricants,sweetening agents, coloring and flavoring agents.

Binders are present in from 1% to about 5% by weight of the tablet.Representative binders include low substituted hydroxypropyl cellulose,polyvinylpyrrolidone, pregelatinized starch and the like.

Disintegrants are present in from 1% to about 17% by weight of thetablet. Representative disintegrants include crospovidone, sodium starchglycolate, starches such as maize starch and dried starch,croscarmellose sodium and cellulose products such as microcrystallinecellulose, microfine cellulose, low substituted hydroxypropylcellulose,either used singly or in admixture.

Lubricants are present in from about 0.25% to about 6% by weight oftablet. Examples of lubricants include magnesium stearate, colloidalsilicon dioxide and the like.

Sweetening agents are selected from amongst natural sweeteners such assugars and artificial sweetening agents such as sodium saccharin oraspartame.

Flavoring agents include fruit flavours, which may be natural orsynthetic.

Tablets of the present invention may be prepared by conventionaltechniques for example wet granulation, compaction or directcompression. In one process, granules are prepared by roller compactionand then milling from a primary blend comprising micronized Cefixime,Mannitol and about one third of the quantity of Magnesium stearate. Thegranules are then blended with the remaining ingredients and theremaining Magnesium stearate to form a secondary blend, which is thencompressed into tablets. The invention is illustrated with followingexamples.

EXAMPLE 1

Quantity per Ingredients tablet (mg) Percent w/w Cefixime trihydrateequivalent 360.86 30.07 to Cefixime (micronized) Mannitol DC 602.4450.20 L-hydroxypropyl cellulose 36.00 3.00 Colloidal silicon dioxide6.00 0.50 Crospovidone 120.00 10.0 Aspartame 18.00 1.50 Lake ColourAllura Red 1.50 0.125 Tutti Frutti flavor 30.00 2.50 Flavor FantasyPermaseal 6.00 0.50 Magnesium stearate 19.20 1.60 Net tablet weight1200.00

Brief manufacturing process: Cefixime (micronized, d₅₀ between 20 μ and120 μ) was sifted through a screen of appropriate aperture size. Theother excipients were also subjected to a sifting process. Cefixime andMannitol along with part quantity of Magnesium stearate were blended andcompacted to get flakes. These flakes were sifted and milled to providegranules. The granules were admixed with the other excipients,lubricated and compressed to obtain tablets.

EXAMPLE 2

Quantity per Ingredients tablet (mg) Percent w/w Cefixime trihydrateequivalent 241.30 30.16 to Cefixime (micronized) Mannitol DC 400.9050.11 L-hydroxypropyl cellulose 24.00 3.00 Colloidal silicon dioxide4.00 0.50 Crospovidone 80.00 10.0 Aspartame 12.00 1.50 Lake ColourAllura Red 1.00 0.125 Tutti Frutti flavor 20.00 2.50 Flavor FantasyPermaseal 4.00 0.50 Magnesium stearate 12.80 1.60 Net tablet weight800.00

Brief manufacturing process: The same process was used as detailed inExample 1.

EXAMPLE 3

Quantity per Ingredients tablet (mg) Percent w/w Cefixime trihydrateequivalent 120.65 30.16 to Cefixime (micronized) Mannitol DC 200.4550.11 L-hydroxypropyl cellulose 12.00 3.00 Colloidal silicon dioxide2.00 0.50 Crospovidone 40.00 10.0 Aspartame 6.00 1.50 Lake Colour AlluraRed 0.50 0.125 Tutti Frutti flavor 10.00 2.50 Flavor Fantasy Permaseal2.00 0.50 Magnesium stearate 6.40 1.60 Net tablet weight 400.00

Brief manufacturing process: The same process was used as detailed inExample 1.

EXAMPLE 4

Quantity per Ingredients tablet (mg) Percent w/w Cefixime trihydrateequivalent 114.32 45.73 to Cefixime (micronized) Mannitol DC 100.4340.00 L-hydroxypropyl cellulose 7.50 3.00 Colloidal silicon dioxide 1.250.50 Crospovidone 7.50 3.00 Sodium saccharin 3.00 1.20 Lake of SunsetYellow 1.00 0.40 Strawberry flavor 7.50 3.00 Flavor Fantasy Permaseal5.00 2.00 Magnesium stearate 2.50 1.00 Net tablet weight 250.00

Brief manufacturing process: The same process was used as detailed inExample 1.

EXAMPLE 5

Quantity per Ingredients tablet (mg) Percent w/w Cefixime trihydrateequivalent 114.32 35.20 to Cefixime (micronized) Mannitol DC 179.7755.31 L-hydroxypropyl cellulose 9.75 3.00 Colloidal silicon dioxide 1.630.50 Aspartame 4.90 1.50 Strawberry flavor 9.75 3.00 Magnesium stearate4.88 1.50 Net tablet weight 325.00

Brief manufacturing process: The same process was used as detailed inExample 1

Bioecuivalence Study

A bioequivalence study was carried out using the tablets comprisingCefixime having a mean particle size greater than 120 μ and tabletscomprising Cefixime having a mean particle size between 20 μ and 120 μas prepared in Example 1 against the commercially available oralsuspension “Suprax” using six healthy volunteers. The study wasmonitored in terms of the AUC and C_(max) achieved with the test productand reference product. AUCs are plots of serum concentrations ofCefixime along the ordinate (Y-axis) against time on the abscissa(X-axis). Generally, the values for AUC represent a number of valuestaken from all the subjects in a population and are, therefore, meanvalues averaged over the entire population. C_(max), the observedmaximum in a plot of serum level concentration of Cefixime (Y-axis)versus time (X-axis) is likewise an average value.

Bioequivalence data for the chewable tablets comprising Cefixime havinga mean particle size greater than 120 μ, against the commerciallyavailable suspension formulation “Suprax” is shown below in Table 1.

Bioequivalence data for the chewable tablets comprising Cefixime havinga mean particle size between 20 μ and 120 μ, against the commerciallyavailable suspension formulation “Suprax” is shown below in Table 2.TABLE 1 BE fasting study data of Cefixime chewable tablets (d₅₀ greaterthan 120μ) against commercially available suspension formulation“Suprax”: Test product: Cefixime chewable tablets (300 mg) (Example 3)Reference product: Cefixime for Oral suspension, 100 mg/5 mL (Suprax)(15 mL) Parameter Cmax (mcg/mL) AUC (0-t) (mcg · h/mL) Test product (T)3.063 25.244 Reference product (R) 3.84 37.122 T/R 79.76 68.00

TABLE 2 BE fasting study data of Cefixime chewable tablets (d₅₀ between20μ and 120μ) against commercially available suspension formulation“Suprax”: Test product: Cefixime chewable tablets (300 mg) (Example 3)Reference product: Cefixime for Oral suspension, 100 mg/5 mL (Suprax)(15 mL) Parameter Cmax (mcg/mL) AUC (0-t) (mcg · h/mL) Test product (T)3.789 29.673 Reference product (R) 3.715 28.837 T/R 100.7 101.6

As can be seen from the data above in Table 1, when the particle size ofCefixime was greater than 120 μ, the T/R ratio for AUC for the chewabletablet was only 68% when compared to the suspension indicating that itis about 30% less bioavailable as compared to the suspensionformulation. In contrast, surprisingly, a similar formulation comprisingCefixime with a mean particle size between 20 μ and 120 μ gave a T/Rratio for AUC of about 100% indicating that the chewable tablet in thiscase had bioavailability equal to that of the suspension formulation. Asimilar trend was noticed when the C_(max) attained in both the caseswas evaluated.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1) A pharmaceutical composition comprising Cefixime, said Cefiximehaving a mean particle size between 20 μ and 120 μ wherein the saidcomposition demonstrates bioequivalence to a suspension of Cefiximetrihydrate 2) The pharmaceutical composition of claim 1 wherein the saidcomposition is a chewable tablet comprising a chewable tablet base andoptionally one or more pharmaceutically acceptable excipients. 3) Thechewable tablet of claim 2 comprising from about 50 to about 300 mgCefixime as trihydrate. 4) The chewable tablet of claim 2 in whichCefixime trihydrate is present from about 10% to about 50% by weight ofthe tablet. 5) The chewable tablet of claim 2 in which Cefiximetrihydrate is present from about 20% to about 40% by weight of thetablet. 6) The chewable tablet of claim 2 wherein the chewable tabletbase is one or more selected from the group comprising of mannitol,xylitol, sorbitol and the like. 7) The chewable tablet of claim 6 inwhich the chewable tablet base is Mannitol. 8) The chewable tablet ofclaim 7 in which mannitol is present from about 30% to about 70% byweight of the tablet. 9) The chewable tablet of claim 8 in whichmannitol is present from about 40% to about 60% by weight of the tablet.10) The chewable tablet of claim 2, which comprises further excipients,selected from amongst binders, disintegrants, lubricants, sweeteningagents, coloring agents and flavoring agents. 11) The chewable tablet ofclaim 10 wherein the binder is present being one or more selected fromthe group comprising of low substituted hydroxypropylcellulose,polyvinylpyrrolidone, pregelatinized starch and the like. 12) Thechewable tablet of claim 11 in which the binder is present from 1% to 5%by weight of the tablet. 13) The chewable tablet of claim 12 in whichthe binder is low substituted hydroxypropylcellulose. 14) The chewabletablet of claim 10 in which the disintegrant is present being one ormore selected from the group comprising of crospovidone, sodium starchglycolate, starches such as maize starch and dried starch,croscarmellose sodium and cellulose products such as microcrystallinecellulose, microfine cellulose, low substituted hydroxypropylcelluloseand the like. 15) The chewable tablet of claim 14 in which thedisintegrant is present from 1% to 17% by weight of the tablet. 16) Thechewable tablet of claim 15 in which the disintegrant is a combinationof crospovidone and low substituted hydroxypropylcellulose. 17) Thechewable tablet of claim 10 in which one or more lubricant is presentselected from the group comprising of colloidal silicon dioxide andmagnesium stearate. 18) The chewable tablet of claim 17 in which thelubricant is present from 0.25% to 6% by weight of the tablet. 19) Thechewable tablet of claim 17 in which the lubricant is a combination ofmagnesium stearate and colloidal silicon dioxide. 20) The chewabletablet of claim 10 in which the sweetening agent is present, the saidagent being a natural or an artificial sweetening agent. 21) Thechewable tablet of claim 20 in which the natural sweetening agent is asugar. 22) The chewable tablet of claim 21 in which the sugar issucrose. 23) The chewable tablet of claim 20 in which the artificialsweetening agent is aspartame. 24) A process of preparation of a solidoral dosage form comprising Cefixime particles, the said processcomprising the steps of optionally micronizing Cefixime such that themean particle size of the Cefixime particles is between 20 μ and 120 μ,blending with other excipients, roll compaction, milling to formgranules, blending to form a secondary blend and compression of thesecondary blend to form tablets. 25) The method of achievingbioequivalence between a solid oral dosage form and a suspension, saidmethod comprising of reduction of the particle size of Cefixime suchthat the mean particle size of the said particles is between 20 μ and120 μ. 26) A pharmaceutical composition comprising Cefixime, saidCefixime having a mean particle size between 20 μ and 120 μ wherein thesaid composition demonstrates AUC and C_(max) in vivo, which issubstantially equivalent to that of a suspension of Cefixime. 27) Achewable tablet comprising Cefixime, said Cefixime having a meanparticle size between 20 μ and 120 μ wherein the said chewable tabletdemonstrates AUC and C_(max) in vivo, which is substantially equivalentto that of a suspension of Cefixime, said chewable tablet furtheroptionally comprising a chewable tablet base and one or morepharmaceutically acceptable excipients.